JPH05506227A - Polymers as contrast agents for magnetic resonance imaging - Google Patents

Abstract

The invention relates to a contrast medium for magnetic resonance imaging comprising, or consisting of, an aqueous solution of suspension of a biocompatible non-crosslinked polymer. The polymer may be synthetic and may further comprise a biocompatible gas. <MATH>

Description

[Detailed description of the invention] Polymers as Contrast Agents for Magnetic Resonance Imaging The present invention relates to the field of magnetic resonance imaging, and further relates to the field of magnetic resonance imaging. In detail, polymers or polymers and contrast agents and/or polymers as contrast agents for magnetic resonance imaging. Or related to use in combination with gas.

Description of prior art Various diagnostic imaging techniques are used to diagnose diseases in humans. use One of the first diagnostic imaging techniques developed was X*.

With X-rays, the resulting image of a patient's body reflects the density of different body tissues. This picture In order to improve the diagnostic applications of diagnostic imaging techniques, contrast agents have been used to visualize the gastrointestinal tract and its surrounding structures. Increases the density between various tissues such as interwovens. Specifically barium and iodine Contrast agents are widely used in X-ray gastrointestinal studies to visualize the esophagus, stomach, intestines and rectum. It will be done. Similarly, these contrast agents can also be used to improve visualization of the gastrointestinal tract. and adjacent tissues such as blood vessels and lymph glands. used for line computed tomography studies. These gastrointestinal contrast agents are edible. Increases the density of the interior of the tract, stomach, intestines and rectum and distinguishes the gastrointestinal system from surrounding tissues.

Magnetic resonance imaging (MHI) is a relatively new technique that, unlike X-rays, does not use ionizing radiation. It is an image diagnostic technology. Like computed tomography, MRI is a cross-sectional image of the body. However, MRI can also be used in any scan plane (i.e. axial, coronal, longitudinal or It also has the advantage of being able to obtain images in the orthogonal plane. Unfortunately, especially when it comes to stomach The full utility of MRI as a diagnostic method of the body in the abdominal and pelvic regions is limited by effective This is hampered by the absence of contrast media. there is no such drug and the use of MRI to differentiate between the intestine, e.g. adjacent soft tissue and lymph glands. is often difficult. If a good contrast agent is available, it can be used as an imaging diagnostic agent. The overall utility of MRI has improved, and the accuracy of this type of diagnosis in the gastrointestinal region has greatly improved. It is raised to

MRI uses magnetic fields, radiofrequency energy, and magnetic field gradients to obtain images of the body. Ru. Differences in contrast or signal intensity between tissues are mainly due to tissue TI and T2 relaxation values. and proton density (actually free water content). Disease caused by the use of contrast media Several possible methods are available for varying the signal strength in the area of the user. for example Contrast agents can be designed to vary T1, T2 or proton density. Wear.

Paramagnetic contrast agents such as Cd-DTPA cause longitudinal relaxation and shorten the TI. this is Increase the signal intensity of T1-weighted images. Superparamagnetic contrast agents such as ferrite are mainly This causes a shortening of T2 and acts on transverse relaxation that reduces the signal intensity of the 12-weighted image. Construction Contrast agents can also be used to increase the signal intensity by changing the proton density. can act by reducing the amount of free water.

Agents that increase the signal intensity compared to the lumen's natural contents are called positive contrast agents. Ru. Many of these have been tested as contrast agents for MRI. These are fats and oils (Newhouse et al., RadiologY 142(P): 246 (1982)), short TI, long T2 and high proton solid 1r density and water proton As a result of various paramagnetic agents increasing the signal by shortening the TI of the to strengthen the signal. A specific example of such a paramagnetic drug is G d - D T P A (Kornmesser et al., Magn, Re5on.

Imaging, 6: 124 (1988), Lan1ado et al., AJR1 50:817 (1988)).

G d-DOTA (Hahn et al., Magn, Re5on, Imaging, 6: 78 (198g)), Gd-oxale) (Runge, V, M, et al., RadiologY, 147: 789 (1983)), Cr. -E D TA (Runge, V, M, etc., Physjol, Chem , Phys.

Mad, NMR, 16: 113 (1984)), Cr-tris-acetate Tylacetonate CCIanton et al., Radiology, 149: 2 38 (1983)), ferric chloride (Young et al., CT, 5:543) (1981)), ferrous gluconate (C1anton et al., Radiolog Y , 153: 159 (1984)), ferrous ammonium citrate and ferrous sulfate. Ittetsu (Wesbey et al., RadiologY, 149: 175 (1983 ), Tschalakoff et al., AJR, 148: 703 (1987)) and iron complexes (Wesbey et al., Magn.

Re5on, Imaging, 3: 57 (1985), Willi ams et al., Radiology, 161:315 (1986)).

On the other hand, agents that reduce the signal intensity from the lumen are called negative contrast agents. Specific examples and Particle iron oxide (Hahn et al., Radiol. ogY, 164:37 (1987), Widder et al., AJR149: 839 (1987)) and gas-generating substances that act by changing proton density. (We] nreb et al., J, Comput, As5ist, Tomogr, 8:835 (1984)) and perfluorocarbon (Mattre y et al., AJR, 148: 1259 (1987)). all paramagnetic substances can cause a decrease in signal intensity due to T2 shortening at sufficiently high concentrations. should also be recognized.

All existing MHI contrast agents have many limitations when used as oral gastrointestinal drugs. receive. Positive contrast agents are applied by intrinsic helical motion and respiratory or cardiovascular effects. increases image noise resulting from motion. Positive contrast agents such as Gd-DTPA Additionally, signal strength is subject to complications due to drug concentration as well as the pulse sequence used. . Contrast from the gastrointestinal tract can be removed unless a sufficiently high concentration of paramagnetic agent is used. Absorption complicates the interpretation of images, especially of the distal part of the small intestine (Kornmesser et al. , Magn, Re5on, Imaging, 6: 124 (1988 )) O-negative contrast agents are relatively insensitive to variations in the pulse sequence and are more consistent. Get contrast. However, at high concentrations, particulates such as ferrite can Magnetization artifacts are particularly evident in the colon, where absorption of ions occurs and superparamagnetic substances are concentrated. can be the cause. Negative contrast agents typically provide better contrast than fat However, in T1-weighted images, positive contrast agents have excellent contrast to normal tissues. Indicates a strike. 71 as most pathological tissues exhibit longer TI and T2 than normal tissues. The emphasized image becomes dark<12 The emphasized image becomes bright. This is an ideal contrast agent is brighter for the 71-enhanced image and must be darker for the 72-enhanced image. shows. All currently available MRI contrast agents used for the gastrointestinal tract are They do not live up to their double standards.

Toxicity is another issue with the contrast agents present. go to any drug However, toxicity is generally dose-related. For ferrite, after oral administration Symptoms of vomiting and transient increases in serum iron often occur. Paramagnetic contrast agent Gd- DTPA is a compound of gadolinium combined with the complexing agent diethylenetriaminepentaacetic acid. It is a machine metal complex. Without coupling, Melt gadolinium ion is very It is toxic. The characteristics of the gastrointestinal tract, where the stomach secretes acid and the intestines release alkali, are used for the gastrointestinal tract. As a result of these pH changes, the free gadolinium is decupapped from the complex Increases the possibility of pulling and separation. Definitely paramagnetic or superparamagnetic contrast agent for the gastrointestinal tract It is important to minimize the dose of be.

Imaging, especially of the gastrointestinal tract, but also of other areas of the body, such as through the vascular system Diagnosis also requires new and/or good contrast agents that are effective for magnetic resonance imaging. It will be done. The present invention is directed toward this important objective.

It consists of an aqueous solution of at least one biocompatible polymer. In some cases, the contrast agent may be should not be mixed with contrast agents, especially paramagnetic, superparamagnetic and/or proton density contrast agents. Ru. The polymer or mixture of polymer and contrast agent may also optionally contain a biocompatible gas. , preferably air, oxygen, carbon dioxide, nitrogen, xenon, neon and/or alkali Consists of gas like gon.

The present invention also relates to a method of obtaining images of regions within a patient's body, particularly of the gastrointestinal tract region of a patient. (f) administering to the patient one or more of the contrast agents described above; (ii) It consists of scanning the patient using magnetic resonance imaging to obtain visible images.

Ultimately, the present invention provides a method for diagnosing the presence of diseased tissue in a patient, particularly in the gastrointestinal region of the patient. (j) administering to the patient at least one of the aforementioned contrast agents; (ii) The patient is scanned using magnetic resonance imaging to obtain visible images of any diseased tissue. It consists of things.

These and other aspects of the invention will be further described from the detailed description below, taken in conjunction with the drawings below. It becomes clear.

Brief description of the drawing Figure 1 is a diagrammatic representation of the contrast agent according to the invention: Figure 2 shows polyethylene glycol% (W /W) versus relaxation rate (1/sec), where polyethylene glyco The polymer is an aqueous solution with or without the presence of Cd-DTPA contrast agent. : Figure 3 is a graph of relaxation rate (1/sec) against dextrose % (W/W). In this case, the dextrose polymer can be used even in the presence of Gd-DTPA contrast agent. Even without it, it is an aqueous solution: Figure 4 shows the relationship between l/T2 ( 1/sec), where the ferrite concentration agent is present in the presence of cellulose polymer. It is an aqueous solution whether or not it is exposed to water (cellulose polymers also absorb carbon dioxide gas). present or not present).

The polymer may be crosslinked if desired. However, the polymer is a cross-saccharide. including. Examples of such polysaccharides include arabinan, fructan, Fucan, galactan, galacturonan, dextran, pastulan, chitin, aluminum Gallose, keratan, fundroitin, dermatan, hyaluronic acid and algin Acids and various other homopolymers or the following aldoses, ketoses, acids or amines: Erythrose, threose, ribose, arabinose, xylose, lyxose , allose, aldrose, glucose, mannose, cuturonic acid, mannuron acid, glucosamine, galactosamine, and neuramic acid. Contains a heteropolymer.

Polyethylene glycol (PEG), a polymer that exhibits high water-binding ability, was developed from this invention. It is particularly suitable for use in the light. High water binding capacity and concomitant amount of free water in solution As a result of the reduction, PEG and similar polymers tend to change the proton density of the solution. It acts on Furthermore, PEG can be used for fractional precipitation of proteins from solution; This may be due in part to the excluded capacity effect produced by this polymer; This excludes the protein from the area of solution occupied by the polymer. , the water spaces between the individual molecules of the polymer, ie the extra-polymer spaces, are concentrated. this The exclusion and concentration effects are shown diagrammatically in Figure 1, where the polymer is represented by a curve and the contrast agent is represented by a black dot.

PEG exhibits limited capacity for ionic complexation, so pre-dynamic concentrations of paramagnetic drugs and the relaxation rate is higher in the mixture with the polymer than in its absence. This results in small paramagnetic chelates such as Gd-DTPA that are highly concentrated.

For these and other reasons, PEG and related polymers are particularly preferred in the present invention. It is a polymer.

Other preferred polymers for diagnostic efficacy include polygalacturonic acid and dextrin. Including Tran.

The polymer of the present invention can be used alone as a contrast agent for magnetic resonance imaging between an aqueous solution and a contrast agent. , such associations are considered to be within the scope of so-called mixtures.

A large number of contrast agents are well known to those skilled in the art, such as paramagnetic, superparamagnetic and droxobenzi. ethylene diamine diacetic acid (HBED), N, N' lononane-N, N', N '-) diacetic acid (NOTA), l, 4,8゜11-tetraazacyclotetradecane -N, N', N'', N''-tetraacetic acid (TETA) and cryptand (i.e. macrocyclic complexes). More preferred complexing agents are DTPA, DOTA, DO3A and Cributane, most preferably DTPA. Preferred proteinaceous macromolecules and Albumin, collagen, polyarginine, polylysine, polyhistidine , γ-globulin and β-globulin. More preferred proteinaceous giant The molecule is albumin, polyal DOTASG(1(I)-DO3A or Gd(I[ I) - ferro or cributane, especially cobalt ferrite and nickel ferrite; In the case of ferrimagnetic contrast agents, such gases are often used to increase the efficacy of the contrast agent. Can be used for air, oxygen, carbon dioxide, nitrogen, xenon, neon and other agents. I can do it. However, the polymer is present at a concentration of at least about 1% by weight. preferably between about 5% and about 50% by weight, and generally between about 5% and about 50% by weight. is most preferably about 40% by weight. of these parameters as recognized by those skilled in the art. The optimum polymer concentration within the range depends on the molecular weight of the polymer, its water binding capacity, and the Of course, this will be influenced by other properties of the particular polymer used. Also, always For magnetic and proton density contrast agents, the contrast agent has a concentration of at least about 0.1 mmol. preferably about 0.5 mmol and about 2 mmol, more preferably about 0.5 mmol and about 2 mmol and most preferably about 1 mmol. For superparamagnetic drugs, Preferably the concentration is at least about 1 micromolar, more preferably about 5 micromolar. between chromol and about 50 micromolar, most preferably about 10 micromolar It is. If gas is used, apply at least about 20 psi to the solution about 1 minute before dosing. It is preferable to supply air, more preferably between about 30 pSj and about 50 psi. and most preferably about 40 psi.

The present invention is useful for diagnosing images of patients in general, and specifically for diagnosing the presence of diseased tissue in patients. It is effective for cutting off The image diagnosis method of the present invention involves administering the contrast agent of the present invention to a patient. , then obtain a visible image of the patient's body region and/or any diseased tissue in that region. This is done by scanning the patient using magnetic resonance imaging. patient's Region refers to the entire patient or a specific area or portion of the patient. The contrast agent is used in the gastrointestinal region. It is particularly useful for obtaining images of the vasculature, but is not readily apparent to those skilled in the art. It can also be used more widely in other methods. Digestive system areas used herein The gastrointestinal tract is the area of the patient defined by the esophagus, stomach, small and large intestines, and rectum. including. The vascular system as used herein refers to the body or organs or part of the blood vessels within the body. show. Most preferably, the patient is a mammal of any kind or human.

As will be recognized by those skilled in the art, administration can be accomplished by a variety of methods including intravascular, oral, rectal, etc. It can be done using shapes. If the region scanned is the gastrointestinal region, this Preferably, the bright contrast agent is administered orally or rectally. f-effect administered The appropriate dose and individual administration method will depend on the age, weight and individual mammal and its territory being scanned. will vary depending on the area and the particular contrast agent of the invention used. Typically used The amount starts at a lower level and is increased until the desired contrast is enhanced. . Various combinations of biocompatible polymers can modify the relaxation phenomenon of contrast agents and improve viscosity, penetration, and used to alter properties such as transparency or mouthfeel (in the case of orally administered materials). Ru. When carrying out the method of the invention, the contrast agent may be used alone or with other diagnostic, therapeutic or combined agents. It can be used in combination with other drugs. Other such agents include flavoring agents or contains excipients such as colorants. Furthermore, if desired, the contrast agent of the present invention may be used in liposomes or can be encapsulated with other delivery vehicles.

If desired, the polymer or polymer and contrast agent and/or gas mixture may be heated in an oven before use. It can be sterilized by tococlaving.

The magnetic resonance imaging techniques used are conventional, for example: M, KeanM, A, Sm4th, Magnetic Re5onance [maging :　Pr1nciples and Applications　(Wjlli am and Wilkins, Baltjmore 1986). Ru. Possible MRI techniques include nuclear magnetic resonance (NMR) and electron spin resonance ( ESR) or are not limited to these. A preferred imaging modality is NMR.

As will be clear to those skilled in the art, when used in magnetic resonance imaging, polymers or The mixture of contrast agent and/or gas depends on the type of polymer used, the polymer Molecular weight, concentration of polymer, type of contrast agent mixed with polymer, selected MRI Depending on Chapter 81 of the Act and the details of the pulse sequence used for MRI imaging, the TI , operated as a T2 or proton density contrast agent, and the mechanism of such operation All are considered to be within the scope of this invention.

The contrast agent of the present invention improves contrast in magnetic resonance imaging, especially in image diagnosis of the gastrointestinal region. It was shown to be very effective as a potentiating agent.

By using the polymer alone or by mixing the polymer according to the invention with a contrast agent. Therefore, in order to obtain the same or, in many cases, a good degree of contrast enhancement effect, A contrast agent with a low total concentration is used. This involves the use of large amounts of potentially toxic contrast media. By avoiding conventional Since no contrast agent is used, there is also an advantage in terms of cost. Furthermore, superparamagnetic particles In the case of negative contrast agents, the ability to use lower doses of contrast agent reduces magnetization artifacts. It will be less. These and other advantages described in the specification of the invention make the disclosure of the invention It will be readily apparent to those skilled in the art upon reading.

The invention is further described in the Examples below. These examples are within the scope of the appended claims. should not be construed as limiting.

Polyethylene glycol (PEG), a polymer with a molecular weight of approximately 8,000, is used in various It was dissolved in water to a concentration (W/W; weight). Then some PEG is added to the aqueous solution. A contrast agent Gd-DTPA was added so that the final concentration of Gd-DTPA was 1 mM.

Next, the relaxation rates of PEG and PEG and G d -DTPA solutions (1/TI and 1/ T2) with Toshiba MR-50A O,5 Tesla (T) whole body scanner It was tested in vitro using The results are shown in Table 1 and FIG. 2. As the results show, P In the presence of EG, the relaxation rates of both water and Gd-DTPA increase.

At best, the relaxation rates are simply added together, i.e. the measured relaxation rate is the sum of the relaxation rates of the individual components. It is expected that the total will be However, the tests in Table 1 and Figure 2 indicate that 40%C in water w/w) The T1 relaxation rate of REG 8000 is 1.35±0.0410.57. The relaxation rate of 1mMGd-DTPA in water is 4.68±0.0910.5T. Indicates that the measurement was made. 40% (w/w) P if velocity is simply added The measured relaxation rate of 1mM Gd-DTPA in EG8000 solution is approximately 4.68+1 ．． It is expected that 35=6.0310.5T. However, surprisingly The results in Table 1 and Figure 2 are pEG/water/Gd-DTPA! The relaxation rate of the compound is actually 12.81±0.7210.5T. Both TI and T2 relaxation rates The relaxation rate of the polymer/Gd-DTPA mixture as the sum of the PEG solution and Gd - It was observed that the relaxation rate was greater than the sum of the relaxation rates of the DTPA solution alone.

The above results indicate that the prekinetic concentration of Gd-DTPA increases in water where it is not bound to a polymer. This occurs as a result of the removal of Gd-DTPA from directly around the PE0 molecule, as shown in It is interpreted that However, the invention is not limited by any theory of operation. is not restricted either.

Table 1 1 [DM Gd-DTPA (0 of PEG3000/water mixture in the absence and presence of D ．． 57i: Relaxation rate at Sample 1 / TI (1/sec) 1 / T2 (1/sec) Water 0.21 f O,04 0,65 + 0.0410% PEG/water 0.41 f O,030,85:t : 0.0320% PEG/water 0.64 f O,021,12+0.06 30% PEG/water 0.96 + 0.02 1.57 + 0.0540%P EG/water 1.35 f O,042,25 + 0.081 mM Gd-DT PA/Water 4.68 f O, 185, flt5 + 0.031O% PEG /Water/ImM Gd-DTPA 5.58=! = 0.23 6.86 =! = 0.0220% PEG/water/1mMGd-DTPA 7.19±0.5 3 8.69f0.0730% PEG/water/1111MGd-DTPA 9. 42:i: 0.58 12.11 + 0.084096 PEG/water/1 mMGd-DTPA I2.81+0.72 17.62+0.15 Example 2 Substantially the same as Example 1 except that polymer dextrose was used in place of PEG. repeated. The results are shown in Figure 3. In the presence of dextrose as the results show The relaxation rate of both water and Gd-DTPA increases.

In addition, as shown in Figure 3, similar to PEG, dextrose and Gd-DTPA solution are The sum rate is greater than the sum of the individual relaxation rates.

Example 3 ImMGd-DTPA, 30% (w/w) PEG8000 and 10% (w/w ) Substantially repeat Example 1, except that an aqueous solution of dextrose was prepared and the TI was reported. I went back. The Tl relaxation rate was actually measured to be 11.67±1.09 (1/sec) 10.5T. .

This shows that different polymers can be used to For example, as shown in Example 3. Sea urchin 1mM Gd-DTPA and 30% PEGF3000 and 10% dextrose The solution of S shows a Tl relaxation rate of 11.67±1.09 (1/sec) 10.5T. ratio Comparatively, 1m! jGd-DTPA and 30% PEC; 8000 solution It showed a sum velocity of 9.42 ± 0.58 (1/s) 10.5T, and 1mMGd-DTPA and a solution of 10% dextrose has a Tl relaxation rate of 2-33 ± 0.0'2 (1/s ) 10.57 is shown.

Example 4 10% (w/w) cellulose, a low toxicity polymer that does not degrade in the gastrointestinal tract, Carbon dioxide was also present with or without the presence of ferrite contrast agent at the same concentration. Example 1 was essentially repeated except that it was used as an aqueous solution with or without addition.

The results are shown in Table 2 and FIG. 4. As the results show, cellulose is also an effective T2 relaxant. It is a Japanese additive, and the T2 relaxation rate of cellulose can be reduced by mixing it with a gas such as carbon dioxide. Improved by Furthermore, the results show that the mixed polymer/ferrite contrast agent mixes with the gas. superior in relaxation rate when compared to polymer or ferrite alone, with or without It is possible to mix cellulose with superparamagnetic contrast agents such as ferrite, as shown in Show that you can do it. For details, see the results for 10mM ferrite and 10% cells after gasification. The T2 relaxation rate of the sample containing loin was higher than that of a 40ml 1J dispersion of ferrite in water. It can be seen that the relaxation rate is high. The direct conclusion is at least 4 factors Therefore, the dose of ferrite administered can be reduced and still achieve the same degree of contrast enhancement. It is possible to This is in that it reduces the possibility of contrast agent toxicity. This is a clear advantage.

Table 2 Relaxation rate of water/ferrite and cellulose/water/ferrite mixtures at 0.5T +10mM ferrite 1.16±0.01 5.45±0.07+20mM Ferrite 1.92±0.03 10.20±0.10+40mM Ferrite 3.60±0.10 20.24±0.43 10% cellulose in water -12, Pressurized with 76±0.08+ gas 0.76±0.01 15.95±0.05 gas +10- Ferrite 1,98±0.03 22.82±0.62 gas +20m M ferrite 2.41±0.03 26.75±0.32 gas + 40mM submersible Ferrate 4.15±0.11 37.42±0.94 measured, 1/T2 is 79 ．． It was measured to be 41±3.20 mmol'5ec-'.

Ta.

7 and 8, substantially the same procedure as in Example 6 except that they were added to the solution in sufficient quantities to raise the I repeated the work. The relaxation rate (1/TI and and I/T2) to Toshiba MRT-50Ao, 5 Tesla (T) It was tested in vitro using a body scanner. The results are shown in Table 3 below.

Table 3 to 0.5 T of water/polygalacturonic acid/Mn(I[) mixtures at various pH levels. relaxation rate at pH64,10±0.192 7.941±0.320pH73,73±0.2 15 6.29±0.240pH84,11±0.546 6.64±0.26 8. Various modifications in addition to those shown and described herein will occur to those skilled in the art from the foregoing description. It will become clear. Such modifications also fall within the scope of the appended claims. It is something that

polymer Polyethylene glycol% (W/W) Dextrose% (w/W) Ferrite concentration (micromolar) Figure 4 abstract A novel contrast agent used in magnetic resonance imaging is described. such contrast agents is a biocompatible polymer alone or a paramagnetic, superparamagnetic, or proton density contrast agent. It consists of a mixture with one or more contrast agents such as. Additionally, polymers or polymer-constructed The mixture with the contrast agent can also be mixed with one or more biocompatible gases and the resulting product Increases the relaxation properties of the agent.

international search report -Inauchi-^-tm11-. PCT/US91102429Per/US9110 2429 ArtUnlt 129 1, Oatms 1-3.8-8.12-16. and 25-30. dr awn to a contrast mediumcampryo■a pol ymer and a method or using 5aid poly mer for magnetl@resonance imaging (MRI), classfled in C1ass 4 24. tabd shout 9゜If, Oaims 4 crystals 10, 22-24.33.　 and 34. drawn to old awn to a contrast ed Gekiho Nit ■ Compri5ingparamagnetlc contrast agen ts, optionally chelated to ≠shio@or a broad class or chelatLng agents and a poly mer and a method or using 5≠奄п@polym er for magneLIc resonance imaging (MR[), cl asdfled in C1ass 12B, su anti-1a Karato @654CΔ.

IIl, Claims 5, 11, 17-21.21. and 32. d raw (o mountain 1wn to a contrast m■рAmuki■ comp mountain - any blocompatible gas and any polymer and a method or usi■@s♂1d polymer for magne LIc resonance imagi ng <MRI), dastlned in 0ass S24. Forearm 1a ss 613° Examiner, One led in the art could Readily practice the 1nven Mr. Jun Kana @or G roup 1 w1thout pracLldng Or Infringing the 1nvenLlo+1(s) or Groups ll-Gekkeki P. 5 ince each or the compoSltlons represented above c onta-]■h　diverse tngrecilengotto@each　b An lndependant Invention and each Is ca pable or supporting its own@patent.

Because these 1 innovations are distinct t for the reasons GLVEN ABO MA■@and ha ve accqulred a 5eparate 5tatus in the ar t as shown by jhetr dlment@classifi cation.

resLrjctjon for examination purposes As Indicated Is proper.

Claims (34)

[Claims] 1. For magnetic resonance imaging made by mixing an aqueous solution of a biocompatible synthetic polymer with a contrast agent Contrast agent. 2. Polymer is polyethylene, polyoxyethylene, polypropylene, Pluron The group consisting of acids, pluronic acid alcohols, polyvinyl and polyvinylpyrrolidone The contrast agent according to claim 1, which is selected from the group consisting of: 3. Claim 2, wherein the polymer is polyethylene which is polyethylene glycol. contrast agent. 4. the contrast agent is selected from the group consisting of paramagnetic, superparamagnetic and proton density contrast agents; The contrast agent according to claim 1. 5. The contrast agent of claim 1, wherein the contrast agent further comprises a biocompatible gas. 6. A contrast agent for magnetic resonance imaging consisting of an aqueous solution of a biocompatible synthetic non-crosslinked polymer. 7. Polymer is polyethylene, polyoxyethylene, polypropylene, Pluron The group consisting of acids, pluronic acid alcohols, polyvinyl and polyvinylpyrrolidone The contrast agent according to claim 6, which is selected from the group consisting of: 8. Claim 7, wherein the polymer is polyethylene which is polyethylene glycol. contrast agent. 9. 7. The contrast agent according to claim 6, wherein the contrast agent further comprises a contrast agent mixed with a polymer. 10. The contrast agent is selected from the group consisting of paramagnetic, superparamagnetic and proton density contrast agents. The contrast agent according to claim 9. 11. 7. The contrast agent of claim 6, wherein the contrast agent further comprises a biocompatible gas. 12. a magnetic material consisting essentially of an aqueous solution of at least one biocompatible non-crosslinked polymer; Contrast agent for air resonance imaging. 13. The polymer is polyethylene, polyoxyethylene, polypropylene, Pluro a group consisting of phosphoric acid, pluronic acid alcohol, polyvinyl and polyvinylpyrrolidone 13. The contrast agent according to claim 12, which is selected from: 14. Claim 13 wherein the polymer is polyethylene which is polyethylene glycol. Contrast agent as described. 15. Non-crosslinked polymers include arabinan, fructan, fucan, galactan, and galac. Turonan, glucan, mannan, xylan, levan, fucoidan, carrageenan , galactocarolose, pectic acid, amylose, pullulan, glycogen, aluminum mylopectin, cellulose, carboxymethyl cellulose, hydroxypropyl Methylcellulose, dextran, pastulan, chitin, agarose, keratan , chondroitin, dermatan, hyaluronic acid, alginic acid and other homopolymers - or erythrose, threose, ribose, arabinose, xylose, riki sauce, allose, altrose, glucose, mannose, growth, idoo galactose, talose, erythrulose, repulose, xylulose, protein Sicose, fructose, sorbose, tagatose, glucuronic acid, gluconic acid , glucaric acid, galacturonic acid, mannuronic acid, glucosamine, galactosamide at least one aldo selected from the group consisting of selected from the group consisting of heteropolymers containing gases, ketoses, acids or amines. The contrast agent according to claim 12. 16. The non-crosslinked polymer is selected from the group consisting of polygalacturonic acid and dextran. The contrast agent according to claim 15, which is selected from the group consisting of: 17. essentially at least one biocompatible polymer and at least one organism A contrast agent consisting of an aqueous solution of a compatible gas. 18. The polymer is polyethylene, polyoxyethylene, polypropylene, Pluro a group consisting of phosphoric acid, pluronic acid alcohol, polyvinyl and polyvinylpyrrolidone 18. The contrast agent according to claim 17, which is selected from: 19. Claim 18 wherein the polymer is polyethylene which is polyethylene glycol. Contrast agent as described. 20. Polymers include arabinan, fructan, fucan, galactan, and galacturona N, glucan, mannan, xylan, levan, fucoidan, carrageenan, gala Tocarolose, pectic acid, amylose, pullulan, glycogen, amylope cutin, cellulose, carboxymethylcellulose, hydroxypropylmethyl Cellulose, dextran, pastulan, chitin, agarose, keratan, condensate Droitin, dermatan, hyaluronic acid, alginic acid and other homopolymers or Erythrose, threose, ribose, arabinose, xylose, lyxose , allose, altrose, glucose, mannose, glucose, idose, ga Lactose, talose, erythrulose, ribulose, xylulose, psicor fructose, sorbose, tagatose, glucuronic acid, gluconic acid, glucose Caricic acid, galacturonic acid, mannuronic acid, glucosamine, galactosamine and At least one aldose selected from the group consisting of neuramic acid, Claims selected from the group consisting of heteropolymers containing toses, acids or amines The contrast agent according to item 17. 21. the polymer is selected from the group consisting of polygalacturonic acid and dextran; The contrast agent according to claim 20. 22. at least one selected from the group consisting of polygalacturonic acid and dextran; A contrast agent made by mixing an aqueous solution of one type of biocompatible polymer with a contrast agent. 23. 23. A contrast agent according to claim 22, wherein the polymer is polygalacturonic acid. 24. The contrast agent according to claim 22, wherein the contrast agent is a paramagnetic ion of Mn(II). . 25. (i) administering to a patient a diagnostically effective amount of a contrast agent according to claim 1; ) from scanning the patient using magnetic resonance imaging to obtain a visible image of the area. method of obtaining images of areas inside a patient's body. 26. (i) administering to a patient a diagnostically effective amount of a contrast agent according to claim 1; ) examine the patient using magnetic resonance imaging to obtain visible images of any diseased tissue in the patient. A method of diagnosing the presence of diseased tissue in a patient consisting of scanning. 27. (i) administering to a patient a diagnostically effective amount of the contrast agent of claim 6; (ii) ) from scanning the patient using magnetic resonance imaging to obtain a visible image of the area. method of obtaining images of areas inside a patient's body. 28. (i) administering to a patient a diagnostically effective amount of the contrast agent of claim 6; (ii) ) examine the patient using magnetic resonance imaging to obtain visible images of any diseased tissue in the patient. A method of diagnosing the presence of diseased tissue in a patient consisting of scanning. 29. (i) administering to a patient a diagnostically effective amount of a contrast agent according to claim 12; i) from scanning the patient using magnetic resonance imaging to obtain a visible image of the area; A method of obtaining images of areas inside a patient's body. 30. (i) administering to a patient a diagnostically effective amount of a contrast agent according to claim 12; i) examine the patient using magnetic resonance imaging to obtain visible images of any diseased tissue in the patient; A method of diagnosing the presence of diseased tissue in a patient. 31. (i) administering to a patient a diagnostically effective amount of the contrast agent of claim 17; i) from scanning the patient using magnetic resonance imaging to obtain a visible image of the area; A method of obtaining images of areas inside a patient's body. 32. (i) administering to a patient a diagnostically effective amount of the contrast agent of claim 17; i) examine the patient using magnetic resonance imaging to obtain visible images of any diseased tissue in the patient; A method of diagnosing the presence of diseased tissue in a patient. 33. (i) administering to a patient a diagnostically effective amount of a contrast agent according to claim 22; i) from scanning the patient using magnetic resonance imaging to obtain a visible image of the area; A method of obtaining images of areas inside a patient's body. 34. (i) administering to a patient a diagnostically effective amount of a contrast agent according to claim 22; i) examine the patient using magnetic resonance imaging to obtain visible images of any diseased tissue in the patient; A method of diagnosing the presence of diseased tissue in a patient.